Benzylamine and phenylethylamine derivatives, processes for preparing the same and their use as medicaments

ABSTRACT

The present invention relates to new phenylamine derivatives, processes for preparing them and their use as pharmaceutical compositions. The phenylamines according to the invention correspond to the general formula I

The present invention relates to new benzylamine derivatives and phenylethylamine derivatives, processes for preparing them and their use as pharmaceutical compositions.

Benzyl- or phenylethylamine derivatives according to the invention correspond to general formula I

wherein

X denotes O, NH, N(CH₃), CH₂;

Y denotes O, NH, N(CH₃), CH₂;

R₁ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, CF₃;

R₂ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, CF₃;

R₃ denotes H, NH₂, NHCOR₅;

R₄ denotes H, CH₂NH₂, CH₂NHCOR₅;

R₅ denotes H, C₁₋₆-alkyl, phenyl, O—(C₁₋₆-alkyl), whilst the phenyl ring may be substituted up to twice by: F, Cl, Br, I, R_(a), OR_(a), CF₃,

R_(a) denotes H, C₁₋₆-alkyl;

A denotes CR₆R₇, CO, SO_(x), O;

x denotes an integer 0, 1 or 2;

R₆ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, —(CH₂)_(y)COOR₈, CF₃, —(CH₂)_(y)OR₈, OR₈;

y denotes an integer 0, 1, 2, 3 or 4;

R₇ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, —(CH₂)_(z)COOR₈, —(CH₂)_(z)OR₈, CF₃;

z denotes an integer 0, 1, 2, 3 or 4, whilst R₆ and R₇ together may optionally form a C₃₋₆-cycloalkyl ring;

R₈ denotes H, C₁₋₆-alkyl;

B denotes C₁₋₆-alkyl, CONR₉R₁₀, Ar, and, if A represents —C(CH₃)₂: CH₂NR₉R₁₀, CH₂NR₉COR₁₁;

Ar denotes phenyl, naphthyl, thienyl, pyridyl—optionally substituted up to twice with R₁₂,

R₉ denotes H, C₁₋₆-alkyl;

R₁₀ denotes H, C₁₋₆-alkyl, whilst R₉ and R₁₀ together with the nitrogen atom may form a ring having 3 to 7 carbon atoms;

R₁₁ denotes H, C₁₋₆-alkyl, —O—(C₁₋₆-alkyl), phenyl;

R₁₂ denotes H, C₁₋₆-alkyl, O—(C₁₋₆-alkyl), F, Cl, Br, I, R_(a), CF₃, CHF₂, C(CH₃)₂-phenylene-OH, COOR_(a), CONR_(a)R_(b), OR_(c);

R_(a) denotes H, C₁₋₆-alkyl;

R_(b) denotes H, C₁₋₆-alkyl, whilst optionally R_(a) and R_(b) together with the nitrogen atom may form a ring having 3 to 7 carbon atoms;

R_(c) denotes H, C₁₋₆-alkyl, COOR_(d), COR_(d) or a group of formula

l, m, n denote an integer 0, 1, 2, 3 or 4 whilst l+m+n≦4;

R_(d) denotes C₁₋₆-alkyl, phenyl,

optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—with the proviso that R₃ and R₄ together cannot denote hydrogen.

Preferred compounds of general formula I are those wherein

X denotes O;

Y denotes O;

R₁ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, CF₃;

R₂ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, CF₃;

R₃ denotes NH₂;

R₄ denotes H;

A denotes CR₆R₇, O;

R₆ denotes H, C₁₋₄-alkyl, CF₃;

R₇ denotes H, C₁₋₄-alkyl, CF₃, whilst R₆ and R₇ together may optionally form a C₃₋₆-cycloalkyl ring;

B denotes phenyl, optionally substituted up to twice with F, Cl, Br, I, R_(a), OR_(c), CF₃;

R_(a) denotes H, C₁₋₆-alkyl;

R_(c) denotes H, C₁₋₆-alkyl, COOR_(d), COR_(d) or a group of formula

l, m, n denote an integer 0, 1, 2, 3 or 4 whilst l+m+n≦4;

R_(d) denotes C₁₋₆-alkyl, phenyl

optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

Unless otherwise stated in specific instances, the general definitions are used in the following sense:

C₁₋₄-alkyl, C₁₋₆-alkyl or C₁₋₈-alkyl generally represents a branched or unbranched hydrocarbon group with 1 to 4 or 6 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s)—preferably fluorine—which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylproypyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups with 1 to 4 carbon atoms, such as methyl; ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, are preferred.

It has been found that the compounds of formula I according to the invention are characterised by their multiplicity of uses in the therapeutic field and by their oral efficacy. Special mention should be made of those possible uses in which the LTB₄-receptor-antagonistic properties play a part. The following deserve particular mention:

arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by non-steroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemias, atherosclerosis and multiple sclerosis.

The new compounds can also be used to treat diseases or conditions wherein the passage of cells from the blood through the vascular endothelium into the tissues is of importance (e.g. metastasis) or diseases and conditions wherein the combination of LTB₄ or another molecule (such as 12-HETE) with the LTB₄-receptor influences cell proliferation (e.g. chronic myeloid leukaemia).

The new compounds may also be used in conjunction with other active substances, e.g. those which are used for the same indications, or for example with antiallergics, secretolytics, β₂-adrenergics, inhaled steroids, antihistamines and/or PAF-antagonists, NSAIDs and glucocorticoids. The substances may be administered topically, orally, transdermally, nasally, by parenteral route or by inhalation.

Pharmacological and biochemical testing of the activity ratios may be carried out using tests as described, for example, in WO 93/16036, pages 15 to 17—to which reference is hereby made.

The therapeutic or prophylactic dose depends, not only on the potency of the individual compounds and the body weight of the patient, but also on the nature and gravity of the disease. For oral administration the dose is between 1 and 500 mg, preferably between 20 and 250 mg. For inhalation the dose is between about 0.5 and 25, preferably between about 2 and 20 mg of active substance.

Inhalable solutions generally contain between about 0.5 and 5% active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalable aerosols, ointments and suppositories.

The examples which follow illustrate some possible formulations for the preparations:

EXAMPLES OF FORMULATIONS

1. Tablets Composition: Active substance according to the invention 20 parts by weight Stearic acid 6 parts by weight Glucose 474 parts by weight

The ingredients are processed in the usual way to obtain tablets weighing 500 mg. If desired the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly.

2. Suppositories Composition: active substance according to the invention 100 parts by weight powdered lactose 45 parts by weight cocoa butter 1555 parts by weight

The ingredients are processed in the usual way to obtain suppositories weighing 1.7 g.

3. Inhalable Powder

Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 μm) optionally with the addition of micronised lactose is packed into hard gelatin capsules in a quantity of 5 mg. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722, to which we hereby refer.

The compounds according to the invention may be produced starting from compounds known from the prior art using, inter alia, the processes described in the Examples which follow. Various other embodiments of the processes will become apparent to the skilled person from the present specification. However, it is expressly pointed out that these Examples and the associated description are provided solely in order to illustrate the invention and not to restrict it.

EXAMPLES OF SYNTHESIS

Compounds according to the invention may be obtained from chloromethyl compounds of formula (II) or corresponding compounds with nucleofugic leaving groups such as halogen, alkyl or aryl sulphonate, with aminoalkylphenols (III)

by reaction with basic adjuvants such as hydroxides, alkoxides, carbonates in polar solvents such as DMF, acetonitrile or ethanol or mixtures thereof (Example 2). (R1 to R4, and A, B and X being defined as hereinbefore; Hal primarily represents halogen or an alkyl or aryl sulphonate group).

Compounds of the invention may also be prepared from the corresponding nitrile compounds by reduction of compounds of formula (IV), e.g. at temperatures of 0-100° C., either by catalytic hydrogenation in alcoholic solvents such as methanol, ethanol or higher alcohols, or DMF or water, with catalysts such as Raney nickel, Pd/C or platinum, and pressures of 760 Torr upwards, or by using hydride reagents—particularly complex hydrides—such as NaBH₄, Ca(BH₄)₂, LiAlH₄ and other aluminium or boron hydrides (Example 1).

(wherein R₁, R₂, A, B, X and Y are as hereinbefore defined).

EXAMPLE 1

4-[[3-[[4-[1-(4-Hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzylamine hydrochloride

2 g of 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-Methylethyl]phenoxy]methyl]phenyl]methoxy]-benzonitrile were dissolved in 50 ml methanol and Raney nickel was added. The mixture was hydrogenated for 6 hours at ambient temperature under normal pressure. The catalyst was removed by suction filtering and the solvent was distilled off. The residue was taken up in methanol, acidified with ethanolic hydrochloric acid and the product was chromatographed over silica gel with dichloromethane/methanol 1:1. After crystallisation with ethyl acetate/ether, 0.5 g of product was obtained as the hydrochloride with a melting point of 161-162° C.

EXAMPLE 2

2-[4-[[3-[[4-[1-phenyl-1-methylethyl]phenoxy]methyl]phenyl]methoxy]]-ethylamine hydrochloride

1.15 g of 4-aminoethyl-phenol were dissolved in 15 ml of methanol and 1.5 g of sodium methoxide was added as a 30% solution in methanol. The solvent was distilled off and the residue was added to a solution of 2.93 g of 3-(4-(2-phenylpropyl)-phenoxymethyl)-benzylchloride in 25 ml of acetonitrile. The mixture was stirred for 3 hours at 60-70° C. The solvent was distilled off, the residue was acidified with alcoholic hydrochloric acid and the product was precipitated with ether. The substance was chromatographed with dichloromethane/methanol 7:3. Yield: 1 g, melting point 145° C.

Salt melting point (° C.) /K_(i) (nM)

hydrochloride 161-162 15.7

hydrochloride 133-134 16.2

hydrochloride 175 13.8

hydrochloride 117-119 11.1

hydrochloride 138-140 21.5

hydrochloride 122-124 1.9

hydrochloride 177-181 28.7

hydrochloride 200-202 1.6

hydrochloride 118-121 27.9

hydrochloride 155 0.55

189-193 59.7

hydrochloride 103-105 32.5

hydrochloride 125-127 50.8

fumarate 143 14.9

240 0.5

methanesulphonate 175 11.4

fumarate 177-178 13.1

126-129 263

fumarate 120 2.85

hydrochloride 145 30.6

fumarate 158-161 4.5

fumarate 208-211 67.3

methanesulphonate 119-121 7.5

sulphate 197-198 0.86

96-98 17.6

100-104 21.9

HCl 227-228 38.6

128-132 21.8

125 10.6

methanesulphonate 175 11.4

150-155° C. 2.4 

What is claimed is:
 1. A compound of formula I

wherein X denotes O, NH, N(CH₃), or CH₂; Y denotes O, NH, N(CH₃), or CH₂; R₁ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, or CF₃; R₂ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, or CF₃; R₃ denotes H, NH₂, or NHCOR₅; R₄ denotes H, CH₂NH₂, or CH₂NHCOR₅; R₅ denotes H, C₁₋₆-alkyl, phenyl, O—(C₁₋₆-alkyl), wherein the phenyl ring is optionally mono- or di-substituted by: F, Cl, Br, I, R_(a), OR_(a), or CF₃, R_(a) denotes H, or C₁₋₆-alkyl; A denotes CR₆R₇, CO, SO_(x), or O; x denotes 0, 1, or 2; R₆ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, —(CH₂)_(y)COOR₈, CF₃, —(CH₂)_(y)OR₈, or OR₈; y denotes 0, 1, 2, 3, or 4; R₇ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, —(CH₂)_(z)COOR₈, —(CH₂)_(z)OR₈, or CF₃; z denotes 0, 1, 2, 3, or 4, wherein R₆ and R₇ together optionally form a C₃₋₆-cycloalkyl ring; R₈ denotes H, or C₁₋₆-alkyl; B denotes C₁₋₆-alkyl, Ar, or CONR₉R₁₀, and, if A represents —C(CH₃)₂: CH₂NR₉R₁₀, or CH₂NR₉COR₁₁; Ar denotes phenyl, naphthyl, thienyl, or pyridyl—optionally mono- or di-substituted with R₁₂, R₉ denotes H, or C₁₋₆-alkyl; R₁₀ denotes H, or C₁₋₆-alkyl, wherein R₉ and R₁₀ together with the nitrogen atom optionally form a ring having 3 to 7 carbon atoms; R₁₁ denotes H, C₁₋₆-alkyl, —O—(C₁₋₆-alkyl), or phenyl; R₁₂ denotes H, C₁₋₆-alkyl, O—(C₁₋₆-alkyl), F, Cl, Br, I, R_(a), CF₃, CHF₂, C(CH₃)₂-phenylene-OH, COOR_(a), CONR_(a)R_(b), or OR_(c); R_(a) denotes H, or C₁₋₆-alkyl; R_(b) denotes H, or C₁₋₆-alkyl, wherein R_(a) and R_(b) together with the nitrogen atom optionally form a ring having 3 to 7 carbon atoms; R_(c) denotes H, C₁₋₆-alkyl, COOR_(d), COR_(d), or a group of formula

wherein l, m, n each denote 0, 1, 2, 3 or 4 with the proviso that l+m+n≦4; R_(d) denotes C₁₋₆-alkyl, or phenyl, the individual optical isomers thereof, a mixture of the individual enantiomers, a free base thereof such or an acid addition salt thereof with pharmacologically acceptable acids, with the proviso that R₃ and R₄ together cannot denote hydrogen.
 2. The compound according to claim 1, wherein X denotes O; Y denotes O; R₁ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, or CF₃; R₂ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, or CF₃; R₃ denotes NH₂; R₄ denotes H; A denotes CR₆R₇, or O; R₆ denotes H, C₁₋₄-alkyl, or CF₃; R₇ denotes H, C₁₋₄-alkyl, or CF₃, wherein R₆ and R₇ together optionally form a C₃-C₆-cycloalkyl ring; B denotes phenyl, optionally mono- or di-substituted with F, Cl, Br, I, R_(a), OR_(c), or CF₃; R_(a) denotes H, or C₁₋₆-alkyl; R_(c) denotes H, C₁₋₆-alkyl, COOR_(d), COR_(d), or a group of formula

wherein l, m, n each denote 0, 1, 2, 3 or 4 with the proviso that l+m+n≦4; R_(d) denotes C₁₋₆-alkyl, or phenyl, the individual optical isomers thereof, a mixture of the individual enantiomers, a free base thereof or an acid addition salt thereof with pharmacologically acceptable acids.
 3. A process for preparing a compound according to claim 1 wherein R₁, R₂, A, B, X, and Y are as defined in claim 1 and R₃, R₄, and the carbon atom to which they are attached form an amine group as defined in claim 1, the process comprising: (a) reacting a benzonitrile derivative of formula IV

wherein R₁, R₂, A, B, and X are as defined in claim 1 and Hal represents, in addition to halogen, a nucleofugic leaving group, with a phenol of formula III

wherein R₃ and R₄ are as defined in claim 1, in the presence of a base in a polar solvent; and (b) isolating the reaction product.
 4. The process according to claim 3, wherein the nucleofugic leaving group is chlorine, alkyl sulphonate, or aryl sulphonate.
 5. The process according to claim 3, wherein the base is a hydroxide, alkoxide, or a carbonate of an alkali or alkaline earth metal.
 6. The process according to claim 3, wherein the polar solvent is dimethylformamide, acetonitrile ethanol, or a mixture thereof.
 7. A process for preparing a compound according to claim 1, wherein R₁, R₂, A, B, X, and Y are defined in claim 1 and R₃, R₄, and the carbon atom to which they are attached form an amine as defined in claim 1, the process comprising: reducing a benzonitrile derivative of formula IV

at a temperature of about 0° C. to about 100° C. to form the corresponding amine of formula I of claim
 1. 8. The process according to claim 7, wherein the reduction is by hydrogenation in a solvent chosen from methanol, ethanol or a higher alcohol, DMF, or water in the presence of a catalyst chosen from Raney nickel, Pd/C, or platinum, at a hydrogen pressure of greater than about 760 torr.
 9. The process according to claim 7, wherein the reduction is accomplished with complex hydrides chosen from the group NaBH₄, Ca(BH₄)₂, LiAlH₄, or other aluminum or boron hydrides.
 10. A pharmaceutical composition of matter comprising a compound according to claim
 1. 11. A method of treating disease in a warm-blooded animal which disease is responsive to compounds with LTB₄-antagonistic activity, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound according to claim
 1. 12. A method of treating arthritis, asthma, chronic obstructive lung disease, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by non-steroidal anti-inflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemias, atherosclerosis, or multiple sclerosis in a warm-blooded animal, the method comprising treating the animal with a therapeutically effective amount of a compound according to claim
 1. 